Significance If early, short-term PMPA therapy in SIV-infected monkeys were able to reducevirus levels, permanently or even transiently, this would support anti-HIV drug treatment as soon as HIV infection is detected by any test. Because the cost of short-term anti-HIV drug therapy would be lower than chronic therapy, short-term drug therapy would be more economically feasible to use, especially in developing nations. Objectives Infection of newborn rhesus macaques with simian immunodeficiency virus is a well-established model for pediatric HIV infection and AIDS. This study was done to determine whether a short-term antiviral regimen given to newborn rhesus macaques early after oral SIV inoculation can prevent or delay cell-free virus in plasma and fatal immunodeficiency. Results Fourteen newborn rhesus were inoculated orally with SIV and all animals became infected. Five days after SIV inoculation (pi), 10 of the 14 SIV-infected neonates were treated once daily with PMPA (30 mg/kg, subcutaneously), a potent inhibitor of the SIV and HIV reverse transcriptase. Four animals (Group A) received PMPA for 14 days and six animals (Group B) received PMPA for 60 days. Four neonates were untreated (Group C). All untreated animals developed persistent high levels of SIV in their plasma and were euthanized with immunodeficiency by 14 weeks pi. In contrast, all PMPA-treated animals developed no clinical signs of immunodeficiency during the 24 week study. In Group B animals, levels of SIV in plasma were lower than in untreated controls both during and after PMPA therapy; in Group A animals SIV in plasma was reduced only during PMPA treatment. Thus, early short-term PMPA treatment can reduce plasma viremia and delay disease in SIV-infected infant rhesus macaques. Future Directions Additional studies with SIV-infected rhesus newborns will be performed to determine the effects of combining short-term PMPA treatment with vaccination against SIV. KEYWORDS SIV, AIDS, antiretroviral therapy, PMPA, pediatric HIV infection